Effectiveness of G-CSF in chemotherapy for digestive system tumors: a systematic review of the Clinical Practice Guidelines for the Use of G-CSF 2022 delineated by the Japan Society of Clinical Oncology.

BACKGROUND: Granulocyte colony-stimulating factor (G-CSF) reportedly reduces the risk of neutropenia and subsequent infections caused by cancer chemotherapy. Although several guidelines recommend using G-CSF in primary prophylaxis according to the incidence rate of chemotherapy-induced febrile neutropenia (FN), the effectiveness of G-CSF in digestive system tumor chemotherapy remains unclear. To address these clinical questions, we conducted a systematic review as part of revising the Clinical Practice Guidelines for the Use of G-CSF 2022 published by the Japan Society of Clinical Oncology. METHODS: This systematic review addressed two main clinical questions (CQ): CQ1: "Is primary prophylaxis with G-CSF effective in chemotherapy?", and CQ2: "Is increasing the intensity of chemotherapy with G-CSF effective?" We reviewed different types of digestive system tumors, including esophageal, gastric, pancreatic, biliary tract, colorectal, and neuroendocrine carcinomas. PubMed, Cochrane Library, and Ichushi-Web databases were searched for information sources. Independent systematic reviewers conducted two rounds of screening and selected relevant records for each CQ. Finally, the working group members synthesized the strength of evidence and recommendations. RESULTS: After two rounds of screening, 5/0/3/0/2/0 records were extracted for CQ1 of esophageal/gastric/pancreatic/biliary tract/colorectal/ and neuroendocrine carcinoma, respectively. Additionally, a total of 2/6/1 records were extracted for CQ2 of esophageal/pancreatic/colorectal cancer, respectively. The strength of evidence and recommendations were evaluated for CQ1 of colorectal cancer; however, we could not synthesize recommendations for other CQs owing to the lack of records. CONCLUSION: The use of G-CSF for primary prophylaxis in chemotherapy for colorectal cancer is inappropriate.

Hindgut and Midgut Neuroendocrine Tumors - Therapeutic Approach.

Introduction: Neuroendocrine tumors of the gastro-entero-pancreatic system have a variety of components, clinical manifestations and prognostic indices according to their anatomical site. Therefore, their diagnostic and management strategies differ a great deal. Prognosis concerning NETs can be poor due to the degree of differentiation, early metastasizing and the high degree of invasiveness. Material and Methods: For the present study, the patient files were evaluated and the parameters of interest were followed. Results: Over the course of 6 years there were 37 patients diagnosed with and treated for NETs, regardless of primary tumor site. There were 9 patients with NETs of the primite mid- and hindgut thusly: 5 cases with colorectal NETs and 4 cases of small bowel NETs. 6 patients benefited from radical surgical treatment, 2 cases with palliative procedures and only one patient with tumor biopsy. The tumors were evaluated according to the 2010 WHO classification based on the number of mitoses and the Ki67 proliferation index. Adjuvant treatment was adapted according to staging and histopathological parameters. Conclusions: Despite recent progress in managing NETs, there are still many controversial aspects regarding the management of these cases, mainly about timing the right sequence of therapy.

Efficacy of Exercise Rehabilitation Program in Relieving Oxaliplatin Induced Peripheral Neurotoxicity.

BACKGROUND: Peripheral neurotoxicity is common in patients with digestive malignancies receiving chemotherapy containing oxaliplatin, and there is still no effective drug to prevent or treat this complication. METHODS: Seventy-nine patients receiving chemotherapy containing oxaliplatin were included, and the relationship between chemotherapy regimens, cycles, and cumulative dose of oxaliplatin and peripheral neurotoxicity was analyzed. Patients were divided into two groups of control or intervention. Twenty-eight patients in the control group received routine chemotherapy care, and 51 patients in the intervention group underwent two-week exercise rehabilitation program. Patients' Functional Assessment of Cancer Therapy/Gynecologic Oncology Group - Neurotoxicity (FACT/GOG-Ntx), functional tests, and Brief Pain Inventory(BPI) scores as well as interference life scores were assessed before intervention and two weeks after the intervention. RESULTS: In the intervention group, 52.9% patients previously exercised regularly. The FOLFOX regimen was more common in peripheral neurotoxicity (73.4%), and the median oxaliplatin cycles for neurotoxicity was 9 (ranging from 1 to 16). The mean cumulative dose of oxaliplatin was 1080.02 ± 185.22 mg, both the cycles and cumulative dose were positively correlated with the occurrence of peripheral neurotoxicity. Compared with control, the scores of FACT/GOG-Ntx, functional tests, and BPI were significantly decreased in the intervention group (p < 0.05). CONCLUSION: Chemotherapy cycles and cumulative doses were in relation with OIN  , and exercise rehabilitation program could effectively alleviate OIN.
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The Safety, Efficacy and Therapeutic Potential of Histone Deacetylase Inhibitors with Special Reference to Panobinostat in Gastrointestinal Tumors: A Review of Preclinical and Clinical Studies.

Histone deacetylase inhibitors (HDACi) have been demonstrated as an emerging class of anticancer drugs involved in regulation of gene expression and chromatin remodeling thus indicating valid targets for different types of cancer therapeutics. The pan-deacetylase inhibitor panobinostat (Farydac®, LBH589) is developed by Novartis Pharmaceuticals and a newly US FDA approved drug for the multiple myeloma. It is under clinical investigation for a range of hematological and solid tumors worldwide in both oral and intravenous formulations. Panobinostat inhibits tumor cell growth by interacting with acetylation of histones and nonhistone proteins as well as various apoptotic, autophagy-mediated targets and various tumorigenesis pathways involved in the development of cancer. The current article summarizes the status of panobinostat in gastrointestinal cancers. Preclinical and clinical data suggest that panobinostat has potential inhibitory activity in hepatocellular, pancreatic, colorectal, gastric and gastrointestinal stromal tumors. Clinical evaluations of panobinostat are currently underway. Herein, we have also reviewed the rationale behind the combination therapy under the trials and possible future prospective for the treatment of GI tumors.

Application of photodynamic therapy in gastrointestinal disorders: an outdated or re-emerging technique?

Photodynamic therapy (PDT) is a promising therapeutic modality that involves the administration of a photosensitizer followed by local illumination with a specific wavelength of light in the presence of oxygen. PDT is minimally invasive, has high selectivity for cancer, and has good patient compliance due to the simplicity of the procedure; therefore, PDT is widely used as a palliative and salvage treatment in patients with various gastrointestinal malignancies. When used as a salvage treatment for locoregional failures after definitive chemoradiotherapy for esophageal cancer, favorable results have been reported. PDT in conjunction with biliary stenting is a promising palliative treatment for unresectable cholangiocarcinoma, and can be used as an advanced diagnostic and therapeutic strategy in peritoneal dissemination of gastric cancer. Recent clinical reports of PDT for treating non-resectable pancreatic cancer also show promising results. To widen the application of PDT, the integration of PDT with molecular imaging and nanotechnology is being extensively studied. Based on these new developments, PDT is likely to re-emerge as a valuable technique in the treatment of diverse gastrointestinal diseases.

Bisphosphonates as potential adjuvants for patients with cancers of the digestive system.

Best known for their anti-resorptive activity in bone, bisphosphonates (BPs) have generated interest as potential antineoplastic agents given their pleiotropic biological effects which include antiproliferative, antiangiogenic and immune-modulating properties. Clinical studies in multiple malignancies suggest that BPs may be active in the prevention or treatment of cancer. Digestive tract malignancies represent a large and heterogeneous disease group, and the activity of BPs in these cancers has not been extensively studied. Recent data showing that some BPs inhibit human epidermal growth factor receptor (HER) signaling highlight a potential therapeutic opportunity in digestive cancers, many of which have alterations in the HER axis. Herein, we review the available evidence providing a rationale for the repurposing of BPs as a therapeutic adjunct in the treatment of digestive malignancies, especially in HER-driven subgroups.

Combination of oxaliplatin plus irinotecan in patients with gastrointestinal tumors: results of two independent phase I studies with pharmacokinetics.

PURPOSE: Two phase I studies of the oxaliplatin and irinotecan combination were performed in advanced gastrointestinal cancer patients to characterize the safety and pharmacokinetics of the regimen. PATIENTS AND METHODS: Patients with a performance status (PS) of < or = 2 and normal hematologic, hepatic, and renal functions received oxaliplatin (2-hour intravenous infusion) followed 1 hour later by irinotecan administered over a 30-minute period, every 3 weeks. Dose levels that were explored ranged from 85 to 110 mg/m(2) for oxaliplatin and 150 to 250 mg/m(2) for irinotecan. Plasma pharmacokinetics of total and ultrafiltrable platinum, irinotecan, SN-38, and its glucuronide, SN-38G, were determined. RESULTS: Thirty-nine patients with gastrointestinal carcinomas (24 with colorectal cancer [CRC], four with pancreas cancer, four with gastric cancer, three with hepatocarcinoma, and four with other) received 216 treatment cycles. Median age was 54 years (range, 21 to 72 years); 95% had PS of 0 to 1; all but six had failed fluorouracil (5-FU) chemotherapy. The maximum-tolerated dose was oxaliplatin 110 mg/m(2) plus irinotecan 200 mg/m(2) in one study and oxaliplatin 110 mg/m(2) plus irinotecan 250 mg/m(2) in the other study. Grade 3 to 4 diarrhea and febrile neutropenia were dose-limiting toxicities; other toxicities included emesis and dose-cumulative neuropathy. Recommended dose for phase II studies is oxaliplatin 85 mg/m(2) and irinotecan 200 mg/m(2). At this dose (12 patients, 65 cycles), grade 3 and 4 toxicities per patient included the following: emesis in 42% of patients, neutropenia in 33% (febrile episodes in 17%), peripheral neuropathy in 25%, delayed diarrhea in 17%, and thrombocytopenia in 8%. Two patients with Gilbert's syndrome experienced severe irinotecan toxicity. No plasmatic pharmacokinetic interactions were detected. Seven partial responses were observed in 24 CRC patients. CONCLUSION: This combination is feasible, with activity in 5-FU-resistant CRC patients. Phase I studies that explore the every-2-weeks schedule, in addition to phase II studies of this schedule (as well as in combination with 5-FU) as second-line therapy of metastatic CRC, are ongoing.

Influence of preoperative administration of omega-3 fatty acid-enriched supplement on inflammatory and immune responses in patients undergoing major surgery for cancer.

OBJECTIVE: Polyunsaturated fatty acid supplementation may produce beneficial effects after surgery. We investigated the influence of preoperative administration of a supplement rich in arginine, omega-3 fatty acids, and RNA, Impact (Japan), on inflammatory and immune responses in patients undergoing major surgery for cancer. METHODS: Patients in the supplement group (n = 12) received 1 L/d of Impact (Japan) for 5 d before surgery, and those in the control group (n = 14) received an ordinary diet without Impact (Japan) before surgery. Plasma levels of omega-3 and omega-6 fatty acids, thromboxane B(2), prostaglandin E(2), inflammatory markers, nutritional markers, cytokines, and cytokine receptors were obtained 5 d before the operation at the starting point of supplementation in the supplement group. Samples were collected on postoperative days (PODs) 0, 1, 3, and 7. RESULTS: After taking the supplement, significant increases in omega-3 fatty acids and rapid turnover proteins were found the day after ending supplementation (POD-0), whereas thromboxane B(2) levels and the ratio of omega-6 fatty acids to omega-3 fatty acids were significantly lower than before supplementation (P < 0.001). On POD-0 only, inflammatory markers and cytokine receptors in the supplement group showed low levels in comparison with the control group (P < 0.05). On POD-1 and POD-3, remarkable decreases in polymorphonuclear leukocyte-elastase and interleukin-8 in the supplement group were observed. CONCLUSION: Our findings suggest that oral administration of a supplement rich in omega-3 fatty acids for 5 d before surgery may improve not only preoperative nutritional status but also preoperative and postoperative inflammatory and immune responses in patients who have cancer.

Raltitrexed (Tomudex) in combination with platinum-based agents and/or anthracyclines: preliminary results of phase I clinical trials.

Three ongoing, dose-escalation, phase I studies are evaluating the combination of raltitrexed with oxaliplatin or anthracyclines (with and without cisplatin). In study 1, patients with advanced solid tumours received 2.0-3.75 mg/m2 raltitrexed, followed 45 min later by 85-130 mg/m2 oxaliplatin (2-h infusion) every 3 weeks. In study 2, patients with advanced oesophageal or gastric adenocarcinoma received 2.0-3.0 mg/m2 raltitrexed with 50 mg/m2 intravenous (i.v.) epirubicin and 60 mg/m2 i.v. cisplatin every 3 weeks. In study 3, patients with advanced or metastatic gastric cancer received 2.5-3.5 mg/m2 raltitrexed followed by 30-60 mg/m2 i.v. doxorubicin every 3 weeks. In all studies, raltitrexed was given as a 15-min infusion. All the combinations evaluated were administered in convenient 3-weekly schedules and were generally well tolerated. Recommended doses for raltitrexed and oxaliplatin are the same in combination as for single-agent use, i.e. 3.0 mg/m2 raltitrexed and 130 mg/m2 oxaliplatin. The recommended dose of raltitrexed in combination with cisplatin and epirubicin is 2.5 mg/m2. No dose-limiting toxicities were observed during co-administration of the full single-agent doses of raltitrexed and doxorubicin (3.0 mg/m2 and 60 mg/m2, respectively); dose escalation is continuing. Preliminary efficacy results were encouraging, particularly for the combination of raltitrexed and oxaliplatin in patients with mesothelioma and advanced colorectal cancer. Preliminary data from these phase I studies suggest that the combination of raltitrexed with platinum-based agents and/or anthracyclines may represent useful regimens for the treatment of patients with advanced cancer. Further studies are required to identify the most effective combinations of raltitrexed with both established and new anticancer agents.

[Combined high dose leucovorin and 5-fluorouracil continuous infusion for head-neck and digestive tract cancers].

OBJECTIVE: To evaluate the feasibility of combined high dose leucovorin plus 5-fluorouracil infusion for head-neck and digestive tract cancers. METHODS: Fifty-six patients with head-neck and digestive tract cancer were treated by combined high dose leucovorin (HD-CF) plus 5-fluorouracil (5-Fu) 48 hour continuous infusion with each patient receiving an average of 3.8 cycles (2-6 cycles). Twenty-five of these 56 patients were untreated and 31 recurrent. Their clinical stages were II 4, III 13 and IV 39. RESULTS: The over all response rate (CR + PR) was 35.7% and the clinical beneficial response rate was 80.4%. The main side effects were peripheral phlebitis, suppression of bone marrow, oral ulcer, nausea and vomiting of grade I to II. CONCLUSION: High dose leucovorin plus 5-fluorouracil 48 hour continuous infusion is useful with favorable cost/utility ratio for head-neck and digestive tract cancer patients. Further studies are warranted.

The role of capecitabine in the management of tumors of the digestive system.

Capecitabine has been developed as a prodrug of FU, with the goal of improving tolerability and intratumor drug concentration through tumor-specific conversion to the active drug. The purpose of this article is to review the available information on capecitabine with respect to clinical efficacy for tumors of the digestive tract, adverse-effect profile, documented drug interactions, dosage and administration, and future directions of ongoing research. Relevant English-language literature was identified through searches of NCI, PubMed, ASCO.org and ESMO, ECCO meetings proceedings.